Endocrine Pharmacology - Insulin

Insulin Overview

Insulin is a peptide hormone produced by the beta cells of the pancreas in the islets of Langerhans. It plays a crucial role in regulating blood glucose levels, allowing cells to absorb glucose for energy or storage. Insulin is essential for maintaining energy homeostasis and is particularly important for the body's utilization of carbohydrates, fats, and proteins.

• Structure: Insulin is composed of two polypeptide chains (A and B chains) linked by disulfide bonds.
• Synthesis: It is initially synthesized as a precursor, preproinsulin, which is processed to proinsulin and finally cleaved to release active insulin and C-peptide.

2. Regulation of Insulin Secretion

Insulin secretion from the pancreas is tightly regulated by multiple factors:

• Blood Glucose Levels: The primary stimulus for insulin release is an increase in blood glucose levels. When blood glucose rises after a meal, beta cells are triggered to release insulin.
• Incretin Hormones: Hormones like GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) released from the gut enhance insulin secretion in response to food intake.
• Autonomic Nervous System: The parasympathetic nervous system stimulates insulin release during feeding, while the sympathetic nervous system can inhibit insulin secretion under stress.
• Amino Acids and Fatty Acids: Increased levels of certain amino acids and fatty acids can stimulate insulin secretion.
• Hormones and Other Signals: Hormones like cortisol, growth hormone, and glucagon can influence insulin release either directly or indirectly.

3. Pharmacokinetics of Insulin

The pharmacokinetics of insulin can vary based on its form (endogenous or exogenous):

• Absorption: Exogenously administered insulin (e.g., injections) is absorbed differently depending on the route, such as subcutaneous (most common), intravenous, or intramuscular. The rate of absorption can also be influenced by factors like the injection site, blood flow, and body temperature.
• Distribution: After absorption, insulin circulates in the bloodstream, binding to insulin receptors on target cells.
• Metabolism: Insulin is primarily metabolized by the liver and kidneys. Around 50% of insulin is removed in a single pass through the liver.
• Half-Life: The half-life of endogenous insulin is very short, typically about 5-10 minutes. Exogenous insulin analogs are modified to have different half-lives, allowing for varied therapeutic effects.

Insulin analogs (such as rapid-acting, short-acting, intermediate-acting, and long-acting insulins) are designed to have specific pharmacokinetic profiles to match physiological needs more closely.

4. Mechanism of Action

Insulin exerts its effects by binding to insulin receptors on target cells, particularly in muscle, liver, and adipose tissue. The insulin receptor is a tyrosine kinase receptor, and the binding of insulin activates the receptor’s intrinsic kinase activity. This activation leads to a cascade of intracellular signaling pathways, primarily the PI3K/Akt pathway, resulting in:

• Glucose Uptake: Insulin promotes the translocation of GLUT-4 glucose transporters to the cell surface, especially in muscle and adipose tissue, facilitating glucose uptake.
• Glycogen Synthesis: Insulin activates enzymes involved in glycogen synthesis, promoting glucose storage in the liver and muscles.
• Lipid and Protein Metabolism: Insulin stimulates lipogenesis and protein synthesis while inhibiting lipolysis and proteolysis.
• Inhibition of Gluconeogenesis: In the liver, insulin suppresses the production of glucose by inhibiting gluconeogenesis and glycogenolysis.

5. Pharmacological Actions of Insulin

Insulin’s pharmacological effects can be broadly categorized based on its metabolic and cellular actions:

• Blood Glucose Lowering: By promoting glucose uptake and storage, insulin effectively lowers blood glucose levels.
• Anabolic Effects: Insulin is an anabolic hormone, promoting the storage of glucose as glycogen, fatty acids as triglycerides, and amino acids as proteins.
• Antilipolytic Effect: In adipose tissue, insulin inhibits the breakdown of stored fats by inhibiting hormone-sensitive lipase.
• Growth-Promoting Effects: Insulin influences growth and cellular proliferation by activating growth-promoting signaling pathways.

In a clinical setting, insulin therapy is used primarily for managing diabetes mellitus. Insulin replacement therapy, with various types and formulations of insulin, is critical in both Type 1 and some cases of Type 2 diabetes to maintain euglycemia (normal blood glucose levels) and prevent complications.

Insulin Preparations

1. Rapid-Acting Insulins

• Examples: Insulin Lispro (Humalog), Insulin Aspart (NovoLog), Insulin Glulisine (Apidra)
• Onset: 10–20 minutes
• Peak: 30–90 minutes
• Duration: 3–5 hours
• Use: Taken right before or right after meals to cover post-meal glucose spikes.

2. Short-Acting Insulins (Regular Insulins)

• Examples: Regular Insulin (Humulin R, Novolin R)
• Onset: 30 minutes to 1 hour
• Peak: 2–4 hours
• Duration: 5–8 hours
• Use: Taken about 30 minutes before a meal to cover mealtime glucose rises.

3. Intermediate-Acting Insulins

• Examples: NPH Insulin (Humulin N, Novolin N)
• Onset: 1–3 hours
• Peak: 4–12 hours
• Duration: 12–18 hours
• Use: Often taken twice daily to provide basal insulin coverage and combined with rapid- or short-acting insulin at meals.

4. Long-Acting Insulins

• Examples: Insulin Glargine (Lantus, Toujeo), Insulin Detemir (Levemir)
• Onset: 1–2 hours
• Peak: Minimal or no peak
• Duration: Up to 24 hours (varies by formulation)
• Use: Provides steady basal insulin levels, typically taken once daily.
• Note:
  • Insulin galargine on s.c. administration, it precipitates and slowly absorbed with delayed onset of action and long acting upto 24 hours with no peak level. It is administered once daily, usually at bedtime.
  • Insulin detemir on s.c administration, it binds to albumin in blood and has prolonged duration of action with minimal peak level. It is given twice daily.

Last modified on: 03/11/2024